Parkinson's disease (PD) is a progressive disorder of the central nervous system that mainly affects motor and other functions. The cardinal clinical features of Parkinson's disease (PD) include resting tremor, rigidity, difficulty in initiating movement and postural instability. These symptoms develop as a result of slow degeneration of dopamine neuron in the substantia niagra resulting in production of less and less dopamine. The loss of dopaminergic neurons in the pars compacta region of the substantia nigra and the inhibition of nigrostriatal dopaminergic pathway results in development of dysfunction of movements. Even though the pathogenesis of PD is poorly understood, studies of the genetic mutations, neuropathology and other factors of PD have provided much insight into the pathophysiology of PD and the progression of this disease. Both oxidative stress and mitochondrial dysfunction have been strongly implicated in cell death. The presence of Lewy bodies (LBs) in the surviving neurons of the substantia nigra is the neuropathological hallmark of PD. The physical characteristics of LBs are round, eosinophilic, intracytoplasmic proteinaceous inclusions and they are found to contain principally polymeric α-synuclein proteins.
Evidence from various studies have consistently implicated iron in the pathophysiology of PD. Iron being the most abundant metal in the human body is particularly found in higher level in the brain and liver. The role of iron in the pathogenesis of PD has been strengthened by several observations. Higher levels of iron are generally found in the brains of PD patients compared to normal brains. Additionally, iron accumulation observed is higher in the substantia nigra region of people afflicted with PD. It is well known that free iron plays a role in generating of oxidative stress leading to dopamine cell death. The generation of hydroxyl radical from free iron occurs by the Fenton reaction (Equation 1). It has also been shown that the presence of iron can initiate aggregation of alpha-synuclein in LBs, implicated in dopamine cell death. The aggregation of alpha-synuclein possibly takes place via conversion of this molecule into β-pleated sheets. Recent studies have shown that overexpression of α-synuclein can form toxic aggregates in the presence of iron. This is believed to contribute to the formation of LBs via production of oxidative stress. Iron released from neuromelanin has also been reported to cause mitochondrial dysfunction and to reduce proteasomal function. All these evidences have further been corroborated by the fact that iron chelators are neuroprotective. Thus, a crucial role of iron in PD pathogenesis has been emphasized because of its capacity to enhance the production of oxygen radicals and accelerate neuronal degeneration. Oxidative stress can facilitate mutant protein aggregation, mimicking proteasomal malfunction. Thus, iron chelators can possibly sequester free iron and thereby prevent its ability to induce oxidative stress as a consequence of reactive hydroxyl radical generationH2O2+Fe2+→OH−+OH.+Fe3+  (Equation 1)
Recently, bifunctional iron chelators were developed where an iron binding 8-hydroxy quinoline moiety was attached to N-propargyl amine and to the piperazine moiety to provide neuroprotective property via reduction of oxidative stress. Two such compounds, 5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)quinolin-8-ol (VK 28) and 5-((prop-2-ynylamino)methyl)quinolin-8-ol (M30), were shown to be antioxidant and neuroprotective in animal experiments.
Accordingly, there is a need for dopamine improved D2/D3 agonist molecules, and in particular, for improved D2/D3 agonist molecules with a capacity to bind to iron.